At present, many attempts have been made to use a protein solution in the form of liquid droplets. Such liquid droplets of a protein solution and technique thereof are applied to a drug delivery method via transmucosal administration and to a biochip and a biosensor requiring an extremely small amount of protein. Furthermore, attention is drawn to a method of forming fine liquid droplets of a protein in controlling protein crystals and screening physiologically active substances (see Japanese Patent Application Laid-Open No. 2002-355025, Allain L R et. al. “Fresenius J. Anal. Chem.”, 2001, Vol. 371, p. 146-150 and Howard E I, Cachau R E “Biotechniques”, 2002, Vol. 33, p. 1302-1306).
Recently, proteins, in particular, enzymes and useful proteins having physiological activities have come to be produced in a large scale by genetic recombination technologies. In these circumstances, a means for forming liquid droplets of a protein may be a useful tool for screening and using novel proteinaceous drugs and developing application fields. Of them, a means for administering various drugs to patients in the form of fine liquid droplets has increased in importance. In particular, a means for administering biological substances including proteins and peptides through the lung becomes important. The lung has lung alveoli whose surface area is as large as 50 to 140 m2 and the epithelium serving as an adsorption barrier, whose thickness is as extremely thin as 0.1 μm, as well as poor enzymatic activity compared to that in the digestive tract. For these reasons, the lung has received attention as a potential administration route in place of an injection route for macromolecular peptide based drugs represented by insulin.
Generally, it is known that the deposition of fine liquid droplets of a drug within the lung varies depending upon the mass median aerodynamic diameter. Of the lung alveoli, to deliver liquid droplets to the lung alveoli present deepest within the lung, liquid droplets having a narrow particle size distribution within 1 to 5 μm must be administered with high reproducibility. Therefore, development of an administration form enabling such an administration and a stable drug preparation are required.
There are some conventional methods for administering a drug preparation within the body, especially, around the respiratory organs. These methods will be described below.
In a metered dose inhaler (MDI) for administering a suspension in aerosol form by using a liquefied non-inflammable gas or flame-retardant gas as a propellant, since the unit volume, that is, the volume of the liquefied gas supplied in a single spray operation time, is regulated, a constant amount of liquid droplets can be sprayed. However, problems still remain unsolved in controlling the size of liquid droplets by regulating the unit volume of the liquefied gas. In addition, it is difficult to say that the propellant is good for health.
In a spray method for a liquid agent containing water or ethanol as a medium, the liquid agent is converted into fine liquid droplets by ejecting it together with a pressurized carrier gas through a capillary. Therefore, it is theoretically possible to control the spray amount of liquid droplets by regulating the amount of the liquid agent to be supplied to the capillary channel. However, it is still difficult to control the size of droplets.
In particular, in the spray method, the pressurized gas used for converting a liquid agent into fine liquid droplets is also used as a gaseous carrier (airflow) for transferring the sprayed fine liquid droplets. Therefore, it is structurally difficult to change an amount of fine liquid droplets (density) floating in the carrier-gas airflow in accordance with intended use.
A method for forming liquid droplets having a narrow particle size-distribution is reported in documents (U.S. Pat. No. 5,894,841 and Japanese Patent Application Laid-Open No. 2002-248171). In this method, extremely fine liquid droplets are formed by a liquid droplet generator based on the liquid ejection principle used in inkjet printing and used. In the liquid ejection in accordance with the inkjet system, an ejection liquid is guided into a small chamber and then physical force is applied to the liquid, thereby pushing the liquid from orifices in the form of liquid droplets. When the liquid is pushed by a thermal transducer such as a thin-film resistor through orifices (ejection ports) formed at the top of the chamber, air bubbles are generated (bubble-jet system and a thermal ink-jet system). The liquid may be pushed by use of a piezo vibrator directly through orifices at the top of a chamber (called piezo inkjet system). The liquid introduction chamber and orifices are integrated into a print head device, which is further connected not only to a liquid supply source but also to a controller for controlling ejection of liquid droplets.
To allow the lung to absorb a drug, in particular, a protein/peptide preparation, it is necessary to accurately control a dose of the drug. In view of this, it is very preferable to form liquid droplets based on the principle of the inkjet system, since the ejection amount can be controlled. In this system, although it is desired to eject a liquid without fails, a protein/peptide solution adjusted only in surface tension and viscosity is not ejected stably and difficult to eject with high reproducibility and efficiency in some cases.